US3682906A - Certain 2 - hydroxymethyl-3-carboxylic acid amidoquinoxaline-di-n-oxides (1,4) - Google Patents

Certain 2 - hydroxymethyl-3-carboxylic acid amidoquinoxaline-di-n-oxides (1,4) Download PDF

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Publication number
US3682906A
US3682906A US880968A US3682906DA US3682906A US 3682906 A US3682906 A US 3682906A US 880968 A US880968 A US 880968A US 3682906D A US3682906D A US 3682906DA US 3682906 A US3682906 A US 3682906A
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United States
Prior art keywords
compound
carbon atoms
compounds
carboxylic acid
hydroxymethyl
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Expired - Lifetime
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US880968A
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English (en)
Inventor
Florin Seng
Kurt Ley
Karl Georg Metzer
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
    • C07D241/52—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • R and R are identical or different and are each hydrogen or an unsubstituted or substituted aliphatic radical, provided that when either R or R is hydrogen the other can be OH or NH
  • the invention further provides a process for the production of such a compound (I) which comprises reacting a lactone of. the formula:
  • R and/or R are lower alkyl, they are preferably methyl, ethyl, n-propyl or isopropyl.
  • R and/or R are unsubstituted or substituted aliphatic radicals, they are preferably straight-chain or branched alkyl or alkylene radicals with up to 18 carbon atoms (most preferably 1 to 4 carbon atoms) and optionally contain a double bond, any substituents in the aliphatic radicals being preferably hydroxyl, alkoxy of 1 to 4 carbon atoms, CN, COO-alkyl wherein alkyl has 1 to 4 carbon atoms, halogen (preferably chlorine), or a phenyl radical in the a, p or w-position.
  • Other suitable aliphatic radicals include cycloaliphatie radicals with 5 or preferably 6 carbon atoms in the ring system, and these may also be similarly substituted.
  • R and/or R When R and/or R are alkyl they can, together with the nitrogen atom, form part of a 5-, 6- or 7-membered heterocyclic ring system which in the case of the 6-membered ring may be in p-position to the nitrogen and may carry oxygen or sulphur as further hetero-atoms, as well as an N-alkyl group having 1 to 4 carbon atoms in the alkyl part.
  • R and R are both hydrogen, while R and R which may be the same or different, are hydrogen, methyl, nor isopropyl, B-hydroxyethyl, [i-methoxyethyl, alkyl-OH (hydroxyalkyl) or -NH (alkylamine).
  • R R and R can all be hydrogen, while R is any one of the radicals just mentioned.
  • Illustrative amines of Formula III are, without limitation thereto, ammonia, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, tert.butylamine, stearylamine, ethanolamine, Z-hydroxypropylamine, B-hydroxypropylamine, 2-methoxyethylamine, cyclohexylamine, 4-methyl-cyclohexylamine, benzylamine, allylamine, dimethylamine, pyrrolidine, hexamethyleneimine, morpholine, thiomorpholine, hydroxylamine, and hydrazine.
  • At least 1 mol of amine is generally employed per mol of lactone. It is possible, but not usually necessary, to use an excess of amine.
  • the reaction is carried out in the temperature range of about 0 to about C., preferably at about 20 to 40 C.
  • the diluent can be either a polar or a non-polar solvent such as water, alcohols of l to 4 carbon atoms, dimethylformamide, dioxan, tetrahydrofuran, dialkyl ethers of 1 to 4 carbon atoms, benzene, toluene or benzene mixtures.
  • a polar or a non-polar solvent such as water, alcohols of l to 4 carbon atoms, dimethylformamide, dioxan, tetrahydrofuran, dialkyl ethers of 1 to 4 carbon atoms, benzene, toluene or benzene mixtures.
  • reaction with morpholine may be represented by the following reaction scheme:
  • the lactone is suspended in a diluent and mixed with at least the equivalent amount of a primary or secondary amine or with ammonia.
  • the reaction is weakly exothermic and after a short time the Z-hydroxymethyl-3-carbonamidoquinoxaline-di-N-oxides( 1,4) separate out as crystals.
  • dimethylformamide is used as the solvent, the reaction products are frequently in solution. In this case the resulting solution can be evaporated in vacuo or mixed with ether, whereupon the 2- hydroxymethyl-3-carbonamidoquinoxaline-di-N-oxide may separate out as crystals.
  • the compounds of the invention show chemotherapeutic activity. Their chemotherapeutic action has been tested in animal experiments (oral and subcutaneous) in the case of acute bacterial infections, and in vitro.
  • the compounds show a very good antibacterial action in both cases, with the active range comprising both gram-negative and gram-positive bacteria.
  • the compounds are active against mycoplasms in vitro.
  • the compounds can be administered both orally and parenterally. In the case of oral use with animals, ingestion through fodder or drinking water is possible.
  • the compounds can also serve as fodder additives in the raising of poultry or other young animals, in order to avoid diseases occurring in raising, and for better fodder utilization.
  • the new medicines can be employed either as such or in combination with pharmaceutically acceptable excipients.
  • Possible forms of administration in combination with various inert excipients include tablets, capsules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like.
  • excipients comprise solid or liquid diluents or carriers including sterile aqueous media as well as various non-toxic organic solvents and the like.
  • the tablets and the like which are possible for oral administration can be provided with sweetening, flavoring and/or coloring agents.
  • the therapeutically active compound should generally be present in a concentration of about 0.5 to by weight of the total mixture, in amounts which are sulficient to achieve the desired dosages.
  • Tablets for oral ingestion can of course contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various other diluents such as starch, preferably potato starch, and the like and binders, such as polyvinylpyrrolidone, gelatin and the like.
  • additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various other diluents such as starch, preferably potato starch, and the like and binders, such as polyvinylpyrrolidone, gelatin and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulphate and talcum can be used for tablet making.
  • the active substance can be used together with various flavor improving agents, coloring agents, emulsifiers and/or together with diluents such as water, ethanol, propylene glycol, glycerin and similar compounds of this kind of combinations thereof.
  • me urn ace E. coli 14 10 E. 0011' A261 10 10 Pseudomonas aerug. 1 100 100 P Bon'n 100 100 Proteus vulgaris sp 10 10 Klebsiella K 10.
  • 10 Klebsiella 8085 5 5 Staph. aurcus Flens Heidelberg.
  • solutions of the active substances in sesame 011 or groundnut oil or in aqueous propylene glycol Compound of formula or NJSI-drmethylforrnamrde can be employed, as can strain (6) (7) (8) sterile aqueous solutions in the case or the water-soluble Mycobacterrum tubcrculoszs HmRv (Dlfeo-TB- compoundsbroth or egg medium) 100 10-100 100
  • Such aqueous solutions should, where necessary, be buffered in the usual manner, and furthermore the liquid diluent should from the start be rendered isotonic by addition of the requisite amount of salt or glucose.
  • Such aqueous solutions are especially suitable for intravenous, intramuscular and intraperitoneal injections. The manufacture of such sterile aqueous media can be carried out in known manner.
  • E. colz', Klebsiella, Staphylococcus aureus, Diplococcus pneumoniae or Streptococcus pyogenes, Proteus mirabzlis and Pseudomonas aeruginosa were used as infection germs.
  • the ED of the compounds which are most active against E. coli C 165 or Staph. aureus 133, for example the compounds of Formulae l, 6, 3, 4, 7, 9, 10, 12, and 13, is between 6 mg./kg. and 300 mg./kg. for a single oral or subcutaneous administration.
  • the LD lies in the dosage range of about 400 mg./kg. to about 3000 mg./ kg. after single oral administration to mice.
  • the substances are thus relatively non-toxic since the relatively less tolerated substances are distinguished by higher activity and are therefore only employed at a lower dosage.
  • the invention therefore also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the new active compounds in admixture with a solid or liquid diluent or carrier.
  • the invention further provides a medicament in dosage unit form comprising at least one of the new active compounds either alone or in admixture with a solid or liquid diluent or carrier.
  • the medicament may include a protective envelope containing the active compound and, if used, the diluent or carrier.
  • medicament in dosage unit form means a medicament as defined above in the form of discrete portions each containing a unit dose, or a multiple or sub-multiple of a unit dose of the active compound or compounds.
  • Such portions may, for example, be in monolithic coherent form, such as tablets, suppositories, pills or dragees; in wrapped or concealed form, such as wrappedpowders, cachets, sachets, or capsules; in ampoules, either free or as a sterile solution suitable for parenteral injection; or in any other form known to the art.
  • the invention also provides animal feedstuifs comprising at least one of the new active compounds in admixture with a fodder.
  • R and R are identical or different and are each hydrogen, lower alkyl or chlorine, and
  • R and R when taken independently are identical or difierent and are each hydrogen, hydroxy, amino unsubstituted alkyl of 1 to 4 carbon atoms, substituted alkyl of 1 to 4 carbon atoms in which the substituent is hydroxy, phenyl, CN, COO-alkyl with 1 to 4 carbon atoms, halogen, amino or alkoxy of 1 to 4 carbon atoms, cycloalkyl of 5 or '6' carbon atoms, or alkenyl of 2 to 4 carbon atoms, provided that when either R or R is hydroxy or amino the other is hydrogen, or
  • R and R taken together with the nitrogen atom to which they are attached form a 5 to 7 membered saturated heterocyclic ring or such ring having as a further hetero ring member oxygen, sulphur or N-alkyl of 1 to 4 carbon atoms.
  • R and R are each methyl, ethyl, n-propyl, isopropyl, hydrogen or chlorine; and R and R are each alkyl of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms substituted by hydroxyl, alkoxy with 1 to 4 carbon atoms, CN, COO-alkyl with 1 to 4 carbon atoms, chlorine, or phenyl in the ,8- or w-position, alkenyl with 2 to 4 carbon atoms or cyclo alkyl with 6 carbon atoms, or R and R taken together with the nitrogen atom to which they are attached, form a to 7-membered saturated heterocyclic ring or such ring having as a further hetero ring member oxygen, sulphur or N-alkyl with 1 to 4 carbon atoms.
  • R and R are hydrogen and R and R are the same or diflerent and are each hydrogen, methyl, n-propyl, isopropyl, fi-hydroxyethyl, fi-methoxyethyl, hydroxyalkyl of 1 to 4 carbon atoms or alkylamine of 1 to 4 carbon atoms.
  • a process for the production of a compound of claim 1 which comprises reacting a lactone of the formula:
  • R R R3, and R have the meaning set forth in claim 1, in a diluent in the temperature range of 0 to C.
  • the amine of Formula III is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, tert.butylamine, stearylamine, ethanolamine, 2-hydroxypropy
  • a process according to claim 26in which the diluent is selected from the group consisting of water, alcohols of 1 to 4 carbon atoms, dimethylformamide, dioxan, tetrahydrofuran, dialkyl ethers of 1 to 4 carbon atoms, benzene, toluene and benzene.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pipe Accessories (AREA)
US880968A 1968-12-11 1969-11-28 Certain 2 - hydroxymethyl-3-carboxylic acid amidoquinoxaline-di-n-oxides (1,4) Expired - Lifetime US3682906A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE1813918A DE1813918C3 (de) 1968-12-11 1968-12-11 2-Hydroxymethyl-3-carbonsäureamido--chinoxalin-M-di-N-oxide, ein Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende antibakterielle Mittel

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US3682906A true US3682906A (en) 1972-08-08

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US880968A Expired - Lifetime US3682906A (en) 1968-12-11 1969-11-28 Certain 2 - hydroxymethyl-3-carboxylic acid amidoquinoxaline-di-n-oxides (1,4)
US00181245A Expired - Lifetime US3801711A (en) 1968-12-11 1971-09-16 Pharmaceutical compositions of quinoxaline-di-n-oxides

Family Applications After (1)

Application Number Title Priority Date Filing Date
US00181245A Expired - Lifetime US3801711A (en) 1968-12-11 1971-09-16 Pharmaceutical compositions of quinoxaline-di-n-oxides

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US (2) US3682906A (de)
AT (1) AT294105B (de)
BE (1) BE742970A (de)
BR (1) BR6914788D0 (de)
CH (1) CH523263A (de)
CY (1) CY764A (de)
DE (1) DE1813918C3 (de)
DK (1) DK126654B (de)
ES (1) ES374464A1 (de)
FI (1) FI51183C (de)
FR (1) FR2025909B1 (de)
GB (1) GB1254340A (de)
IL (1) IL33364A (de)
MY (1) MY7400294A (de)
NL (1) NL6918463A (de)
NO (1) NO125186B (de)
SE (1) SE356300B (de)
YU (1) YU303969A (de)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3904630A (en) * 1973-03-08 1975-09-09 Riker Laboratories Inc 8-n-methylpiperazinyl-n'-carbonyldibenzo-bicyclooctadiene and salts thereof
US3907994A (en) * 1971-04-20 1975-09-23 Pfizer Substituted alkyl esters quinoxaline-di-N-oxide-2-carboxylic acid as growth promoting agents
US3948911A (en) * 1974-11-19 1976-04-06 Pfizer Inc. Substituted quinoxaline-2-carboxamide 1,4-dioxides
US4228283A (en) * 1978-11-24 1980-10-14 Marxer S.P.A. Process for preparing pure 2-methyl-3-(β-hydroxyethylcarbamoyl)quinoxaline 1,4-di-N-oxide, and other compounds similar thereto

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3643965C1 (de) * 1986-12-22 1988-02-11 Siegenia Frank Kg Ausstellvorrichtung fuer den Fluegel eines Fensters,einer Tuer od.dgl.

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3907994A (en) * 1971-04-20 1975-09-23 Pfizer Substituted alkyl esters quinoxaline-di-N-oxide-2-carboxylic acid as growth promoting agents
US3904630A (en) * 1973-03-08 1975-09-09 Riker Laboratories Inc 8-n-methylpiperazinyl-n'-carbonyldibenzo-bicyclooctadiene and salts thereof
US3948911A (en) * 1974-11-19 1976-04-06 Pfizer Inc. Substituted quinoxaline-2-carboxamide 1,4-dioxides
US4228283A (en) * 1978-11-24 1980-10-14 Marxer S.P.A. Process for preparing pure 2-methyl-3-(β-hydroxyethylcarbamoyl)quinoxaline 1,4-di-N-oxide, and other compounds similar thereto

Also Published As

Publication number Publication date
FI51183B (de) 1976-08-02
DK126654B (da) 1973-08-06
US3801711A (en) 1974-04-02
IL33364A0 (en) 1970-01-29
DE1813918B2 (de) 1978-06-08
CY764A (en) 1974-11-07
IL33364A (en) 1973-07-30
CH523263A (de) 1972-05-31
DE1813918A1 (de) 1970-06-25
ES374464A1 (es) 1972-04-16
MY7400294A (en) 1974-12-31
SE356300B (de) 1973-05-21
NL6918463A (de) 1970-06-15
AT294105B (de) 1971-11-10
NO125186B (de) 1972-07-31
BE742970A (de) 1970-06-11
GB1254340A (en) 1971-11-17
DE1813918C3 (de) 1979-02-15
FR2025909A1 (de) 1970-09-11
YU303969A (en) 1976-03-31
FI51183C (fi) 1976-11-10
BR6914788D0 (pt) 1973-03-08
FR2025909B1 (de) 1973-07-13

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